Disturbances in circadian rhythms and sleep patterns are a common problem in patients with Alzheimer's disease (AD), and interestingly, these changes already occur in patients with mild cognitive impairment. Although originally assumed to be side effects, recent studies suggest that disruptions of circadian rhythms may actively contribute to the pathology of AD, albeit via mechanisms that are unclear. Circadian clocks are present in most organisms and their underlying molecular mechanisms are highly conserved. In general, daily rhythms in behaviors such as sleep and memory weaken with age and also the molecular clock mechanisms are affected by aging in both, Drosophila and humans. In addition, both the Amyloid Precursor Protein (APP) and the secretases that generate its proteolytic fragments are conserved in Drosophila and transgenic flies that express human APP695 or its fragments have been generated. Drosophila therefore provides a uniquely suited model for defining mechanistic connections between the circadian clocks, age, and AD. Using Drosophila, we recently found that expressing only the C-terminal domain of APP (AICD) causes memory deficits and disrupts sleep/activity patterns. It also interfered with the expression of core clock genes. In addition, we observed that the nuclear localization of the AICD showed rhythmic changes in specific neuronal populations, including the Kenyon cells that are required for learning and memory formation and the neurons of the central pacemaker, whereby this pattern was disrupted with age. We also found rhythmic changes of nuclear AICD in the central pacemaker of mice. We therefore hypothesize that the age-related changes in the circadian clock result in a misregulation of the nuclear localization of the AICD, which in turn misregulates clock gene expression. Notably, it has been described in mammalian cells that the nuclear translocation of the AICD predominantly occurs after ?-processing, as has been described in spontaneous AD. Therefore, interactions between the AICD and the circadian clock would be further disrupted in AD patients by increased nuclear translocation of the AICD, resulting in progressively worsening sleep and circadian disruptions in AD patients. Furthermore, changes in the activity of the AICD may contribute to the cognitive decline in AD patients either by directly affecting memory genes or indirectly by disrupting circadian rhythms. To obtain insight into the connection between the AICD and circadian clocks, this proposal will determine how day-night changes in the nuclear localization of the AICD are controlled, how this is may be affected in AD, and to what extent this may contribute to AD. To address these aims, we will use a combination of experiments in flies and mice, taking advantage of the strengths of each model. Public Heath Relevance: The disruptions in sleep pattern and circadian rhythms connected with AD have deleterious effects for the patients and indirectly also affect the health of many caregivers. Defining the role of the AICD in regulating circadian clocks and sleep will provide the basis for developing treatment strategies that could ameliorate or prevent this aspect of AD and possibly also improve the cognitive decline in AD patients.